PROJECT ABSTRACT Cognitive impairment (CI) in patients with advanced chronic kidney disease (CKD) poses a substantial U.S. public health burden, affecting up to 2 million older people with CKD. Both lower estimated glomerular filtration rate (eGFR) and increased albuminuria, a marker of systemic vascular endothelial function, are associated with CI and structural MRI changes. Stroke prevalence is 4 times higher in advanced CKD than in non-CKD, and white matter hyperintensity (WMH) volume and cerebral atrophy are increased. In ADNI, lower eGFR is associated with decreased hippocampal volume, consistent with Alzheimer?s disease. Yet, the natural history, contributing factors, and brain abnormalities associated with cognitive decline in CKD are poorly understood. To address these gaps, we recruited a cohort of 433 adults enriched with advanced CKD (mean eGFR 34; non-dialysis) and 141 non- CKD controls in the BRain In Kidney disease - BRINK study - and followed them for a median of 2.5 years with serial cognitive testing, laboratory tests, and brain MRI. We propose that CKD and its brain sequelae represent a model of accelerated cerebrovascular disease and brain aging, with high rates of hypertension (>90%), diabetes (50%), inflammation, and oxidative stress, driving parallel trajectories of microvascular endothelial dysfunction in the kidney and brain, and secondary neurodegenerative changes. Our primary goal is to extend BRINK and obtain 3 and 5 year brain MRIs to characterize cognitive decline and Alzheimer?s disease- and cerebrovascular-related MRI brain changes over 5 years. Our preliminary data demonstrate that eGFR < 30 was associated with moderate/severe CI at baseline, and delayed memory was most affected, as seen in Alzheimer?s disease. On brain MRI they also had more strokes, WMH and worse white matter integrity. Importantly, high serum phosphorus and low hemoglobin, two common and treatable CKD- related factors, were associated with worse cognitive function and more severe brain MRI changes. Guided by our cross- sectional findings, we will pursue these longitudinal Specific Aims:1) Characterize longitudinal changes in global cognitive function and cognitive domains by eGFR level, 1a) Estimate the associations between change in CKD-related factors and change in cognitive function, 2) Determine the rate of cortical thinning, accumulation of WMHs, infarcts, change in WM integrity and perfusion by eGFR levels; 2a) Estimate the associations between change in CKD-related factors and MRI changes, and 3) Measure the longitudinal association between changes in MRI and cognitive decline over 5 years. This study is innovative by utilizing longitudinal structural MRI to characterize and quantify vascular and Alzheimer?s disease changes and their relation with cognitive trajectories in a cohort enriched with advanced CKD. Our work is significant because it will inform the natural history of cognitive decline and associated brain pathology in CKD and their contributors. It will have impact by a) identifying CKD patients at greatest risk for CI for clinicians, and the timing of potential interventions against cognitive decline such as phosphate binders or novel anemia agents.